Summary: Funds are requested for a 6 MeV/amu linear accelerator (linac), which will be used to generate ion beams spanning a wide range of radiation qualities having penetrations of up to 1 mm in tissue. These beams will then be focused into microbeams (beam diameter of a few microns) or millimeter-sized beams, allowing systematic mechanistic studies of tumor responses and normal-tissue responses relating to contemporary heavy-ion beam radiotherapy. The studies that will be facilitated by the linac are mechanistically- motivated and do not focus explicitly on specific protocols for heavy-ion cancer radiotherapy. The linac will be located at the Radiological Research Accelerator Facility (RARAF) at Columbia University which is an NIH- funded National Biomedical Technology Resource Center dedicated to understanding the radiobiological mechanisms by which different types of radiation affect living matter. There has been increasing recent interest from the radiation therapy and the radiation biology communities in heavy charged-particle radiotherapy, particularly carbon ions, to treat hard-to-treat high-risk tumors, particularly those that have already spread beyond the primary site. These particles deposit energy in a more spatially-dense way (?high LET?) than do X rays or protons. Examples of tumors that have been shown clinically to benefit from high-LET radiation therapy are locally advanced pancreatic tumors, late-stage prostate tumors, and locally recurrent rectal tumors. Based on their efficacy in treating tumors that have spread beyond the primary site, it is reasonable to assume that that the high-LET radiations are eliciting a long-range response, through bystander, abscopal or immunological mechanisms, of a type that may not be induced by conventional radiotherapy. In summary, there is a great deal of interest in the radiotherapy / radiobiology community in trying to understand the mechanisms underlying this heavy-ion high-LET induced long-range signal transduction, particularly in the context of hard-to treat tumors. This is reflected in the range of projects in this application, that include high-LET mechanistic studies for pancreas (Olive), melanoma (Guha), prostate (Shen), breast (Demaria), as well as normal tissue sparing (Fornace), and bystander-effect range estimation (Brenner). Microbeams and millimeter-sized beams, which are produced at RARAF, allow the energy deposition to be highly localized, and so represent an ideal tool to study long-range damage signaling mechanisms. Using the current 2.5 MeV/amu accelerator at RARAF, the spatial range of the particles that can be produced is sufficient only to irradiate cellular monolayers or extremely thin tissues. However the long-range damage signal transduction endpoints of contemporary interest here need to be studied with in-vivo models and 3-D tissue models, which are too thick to be penetrated by 2.5 MeV/amu ions. Thus the spatial penetration of the charged particles needs to be increased, by increasing the energy the particle accelerator. To meet the needs of the users, the available range of the high-LET charged particles needs to be increased by factors of 3 to 4 - requiring ion energies at RARAF of 6 MeV/amu.